Antiviral immune responses: triggers of or triggered by autoimmunity?
ABSTRACT The predisposition of individuals to several common autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, is genetically linked to certain human MHC class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins, as well as the geographical distribution of disease risk, suggest the involvement of environmental factors in the development of these diseases. Among these environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. In this Review, we outline the mechanisms by which viral infection can trigger autoimmune disease and describe the pathways by which infection and immune control of infectious disease might be dysregulated during autoimmunity.
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ABSTRACT: Autoimmune reactions involving cytochrome P4502E1 (CYP2E1) are a feature of idiosyncratic liver injury induced by halogenated hydrocarbons and isoniazid, but are also detectable in about one third of the patients with advanced alcoholic liver disease (ALD) and chronic hepatitis C (CHC). In these latter the presence of anti-CYP2E1 auto-antibodies is an independent predictor of extensive necro-inflammation and fibrosis and worsens the recurrence of hepatitis following liver transplantation, indicating that CYP2E1-directed autoimmunity can contribute to hepatic injury. The molecular characterization of the antigens recognized by anti-CYP2E1 auto-antibodies in ALD and CHC has shown that the targeted conformational epitopes are located in close proximity on the molecular surface. Furthermore, these epitopes can be recognized on CYP2E1 expressed on hepatocyte plasma membranes where they can trigger antibody-mediated cytotoxicity. This does not exclude that T cell-mediated responses against CYP2E1 might also be involved in causing hepatocyte damage. CYP2E1 structural modifications by reactive metabolites and molecular mimicry represent important factors in the breaking of self-tolerance against CYP2E1 in, respectively, ALD and CHC. However, genetic or acquired interferences with the mechanisms controlling the homeostasis of the immune system are also likely to contribute. More studies are needed to better characterize the impact of anti-CYP2E1 autoimmunity in liver diseases particularly in relation to the fact that common metabolic alterations such as obesity and diabetes stimulates hepatic CYP2E1 expression. Copyright © 2014. Published by Elsevier B.V.Redox biology. 11/2014; 3C:72-78.
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ABSTRACT: Although dogma predicts that under normal circumstances potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, islet antigen-reactive B lymphocytes are known to play a crucial role in the development of autoimmunity in Type 1 Diabetes (T1D). Thus participation of these cells in T1D may reflect escape from silencing mechanisms. Consistent with this concept we found that in healthy subjects, high affinity insulin-binding B cells (IBCs) occur exclusively in the anergic BND compartment. Antigen receptors expressed by these cells are polyreactive and have N-region additions, Vh usage, and charged CDR3 regions consistent with autoreactivity. Consistent with a potential early role in autoimmunity, these high affinity insulin-binding B cells are absent from the anergic compartment of some first degree relatives, and all pre-diabetic and new-onset (<1yr) T1D patients tested, but return to normal levels in individuals diabetic for >1 year. Interestingly, these changes were correlated by transient loss of the entire BND compartment. These findings suggest that environmental events such as infection or injury may, by disrupting B cell anergy, dispose individuals toward autoimmunity, the precise nature of which is specified by genetic risk factors, such as HLA alleles. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.Diabetes 12/2014; · 7.90 Impact Factor
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ABSTRACT: Intrathecal specific antibodies in multiple sclerosis (MS), core of several disease models, are functionally ambiguous. Parallel investigation of cerebrospinal fluid (CSF) and aqueous humor (AH) from 22 MS patients showed similar immune reactions in both compartments but in the individual patient we observed arbitrarily varying differences for specific antibody- (12/14), oligoclonal IgG- (7/8) and isotype patterns. Properties of polyspecific antibodies are consistent with B cells immigrating affinity-maturated, isotype-specific, producing low amounts of antibodies without local target antigen in the brain. A local, arbitrarily varying, specificity-independent, self-organizing B cell activity questions actual disease models for MS and may explain the emerging discontinuity of neuropathology and symptoms in space and time. Copyright © 2014 Elsevier B.V. All rights reserved.Journal of Neuroimmunology 11/2014; 278. · 2.79 Impact Factor
Chronic Fatigue Syndrome:
An Overview of the Canadian
Bruce M. Carruthers
Marjorie I. van de Sande
A Clinical Case Definition
and Guidelines for
The Canadian Consensus Document on ME/CFS
Our comparison study examined differences between patients meeting the Canadian clinical
and the Fukuda et al. criteria for ME/CFS, with people who had chronically fatiguing illness
explained by a psychiatric condition. The Canadian Clinical Criteria selected patients with
more physical functional impairment, more fatigue/weakness, neurocognitive and neurological
symptoms and had more variables that significantly differentiated them from the psychiatric
comparison group than did the Fukuda et al. criteria. The findings do suggest that the Canadian
criteria point to the potential utility in designating postexertional malaise and fatigue, sleep
dysfunction, pain, clinical neurocognitive, and clinical autonomic/neuroimmunoendocrine
symptoms as major criteria.
The selection of diagnostic signs and symptoms has major implications for which individuals
are diagnosed with ME/CFS and how seriously the illness is viewed by health care providers,
disability insurers, rehabilitation planners, and patients and their families and friends. I hope
the results of this comparison study will encourage more physicians to USE THE CANADIAN
Leonard A. Jason, Ph D
Director: Center for Community Research, DePaul University, Chicago IL
Board of Directors: American Association for Chronic Fatigue Syndrome
The Canadian Clinical Case Definition has brilliantly rewritten the guidelines to capture, at
last, what ME/CFS is really all about. It is not that patients are fatigued. Healthy people get
fatigued. Rather the definition specifically selects patients who worsen with exercise. This
takes the emphasis away from the subjective sensation of “fatigue” and forces one to clearly
describe the connection between fatigue and activity. This also embraces mental fatigue (loss
of cognitive function and alertness) as well as physical fatigue (lack of energy and strength,
often felt in the muscles). The patient must become symptomatically ill after exercise and
must also have evidence of neurocognitive, neuroendocrine, dysautonomic (e.g. orthostatic
intolerance), and immune malfunction.
TheAdelaide Forum agreed to UNANIMOUSLYEMBRACETHE CANADIANCASEDEFINITION
with a strong recommendation that it also be taken up by ME/CFS societies.
(Excerpt from the final address at the Adelaide Forum, Australia, 2005)
Michael Barratt, MBBS, FRCPA
In my opinion, and in the opinions of the other doctors at the Environmental Health Clinic, the
ME/CFS Consensus Document is EXTREMELY PRACTICAL AND USEFUL. We have used
it repeatedly in helping to develop comprehensive individual treatment plans in collaboration
with patients. At the behest of the Ontario College of Family Physicians' (OCFP) Environmental
Health Committee, and with approval of the publisher, the consensus diagnostic checklists
were posted on the OCFP website. We also use the diagnostic criteria, checklists, and
treatment suggestions as teaching tools in the OCFP's Environmental Health Day at their
Annual Scientific Assembly.
Lynn Marshall, MD, FAAEM, FRSM
Medical Director: Environmental Health Clinic,
Sunnybrook & Women's College Health Sciences Centre
Member: Environmental Health Committee, Ontario College of Family Physicians
Lecturer: University of Toronto Department of Family and Community Medicine
Assistant Professor of Family Medicine: Northern Ontario School of Medicine
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome:
A Clinical Case Definition and Guidelines for Medical Practitioners
An Overview of the Canadian Consensus Document
Bruce M. Carruthers, M.D., C.M., FRCP(C)
Marjorie I. van de Sande, B. Ed., Grad. Dip. Ed.
© Copyright 2005 by Carruthers B.M. and van de Sande M.I.
All rights reserved. No part of this work may be reproduced, utilized, or transmitted in any form, electronic or mechanical,
including photocopying, microfilming, and recording, or by any information storage and retrieval system, or by any means
whatsoever without prior written permission from the authors. In our efforts to make physicians aware of the Consensus
Document and ensure that patients receive an accurate diagnosis and appropriate treatment in a timely fashion, the authors
may consider requests to reproduce this booklet providing ALL of the following conditions are met. This booklet must
be reproduced in its entirety, with no additions, deletions, or changes to this booklet and its contents in any
manner whatsoever; no profit is made by any individual, organization, company, university, or otherwise; and
the authors are credited as the source. In your written request to reprint this booklet please state that you agree to all
of the above conditions and indicate how you intend to use the booklet.
The preparation of this work has been undertaken with great care to publish reliable data and information. However, the
authors are not responsible for any errors contained herein or for consequences that may ensue from use of materials or
information contained in this work. This work does not endorse any commercial product.
The National Library of Canada CataloguinginPublication Data:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical
Practitioners. An Overview of the Canadian Consensus Document. Carruthers, Bruce M., van de Sande, Marjorie I.
Soft cover, alkaline paper. Includes authors’ affiliations, table of contents, 1. Myalgic Encephalomyelitis/Chronic
Fatigue Syndrome (ME/CFS) – Clinical Definition/Diagnostic Criteria, 2. Diagnosis, Differential, 3. Clinical
Diagnostic Guidelines, 4. Treatment Guidelines. Copyright 2005 by B. M. Carruthers and M. I. van de Sande.
Published by: Carruthers & van de Sande
Correspondence to: Dr. Bruce M. Carruthers, email: firstname.lastname@example.org
#2, 3657 West 16 Ave, Vancouver, B.C. V6R 3C3, Canada
Reprint permission requests to: Marjorie van de Sande, email: email@example.com
151 Arbour Ridge Circle N.W., Calgary, Alberta T3G 3V9, Canada
Cover Design by Robert J. van de Sande, B. Sc, E.E.
Cover Pictures (top to bottom): Xenon SPECT scan reveals pronounced worsening of hypoperfusion
following exercise; PET scan reveals decreased glucose utilization; sMRI voxelbased morphometry technique
indicates the volume of gray matter of the brain is significantly reduced and there is an average of 8% reduction
of brain tissue, although not discernable by the naked eye; and the bottom two pictures using qEEG topography
indicate the electrical sources in the gray matter (cortex). ME/CFS patients have increased sources (indicated in
red) in the left hemisphere whereas the controls have increased sources (indicated in green) in the right
hemisphere in the frontal and superior temporal cerebral regions in beta frequencies. Patients’ reduced sources
in the right hemisphere may be due to interference with the left brain inhibitory regulation of the right
hemisphere during cognitive processing.
This booklet is an Overview of
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome:
Clinical Working Case Definition, Diagnostic and Treatment Guidelines
A Consensus Document
Bruce M Carruthers, Anil Kumar Jain, Kenny L De Meirleir, Daniel L Peterson, Nancy G Klimas, A
Martin Lerner, Alison C Bested, Pierre FlorHenry, Pradip Joshi, AC Peter Powles, Jeffrey A
Sherkey, Marjorie I van de Sande.
Journal of Chronic Fatigue Syndrome 11(1):7115, 2003. ISBN: 078902279 © Haworth Medical Press Inc.
This journal is available from The Haworth Document Delivery Service: Phone (Canada & USA) 8007225857.
Email address: firstname.lastname@example.org http://www.HaworthPress.com
Authors and Affiliations: ME/CFS Consensus Document
Bruce M. Carruthers, MD, CM, FRCP(C): Specialist in Internal Medicine, Vancouver, B.C., Canada
Anil Kumar Jain, B Sc, MD: Ottawa Hospital, Ottawa, ON, Canada
Kenny L. De Meirleir, MD, Ph D: Professor of Physiology and Medicine (KDM, IC, PDB); Director of the
Human Performance Laboratory and member of the Vakgroep Internal Medicine; Vrije Universiteit
Brussel, Brussels, Belgium
Daniel L. Peterson, MD: Specialist in Internal Medicine, Affiliate of the Sierra Internal Medicine Associates,
Incline Village, NV, USA; ME/CFS researcher and clinician; a board member of the American
Association of Chronic Fatigue Syndrome; and member of the International Chronic Fatigue Syndrome
Nancy G. Klimas, MD: Clinical Professor of Medicine in Microbiology/Immunology/Allergy and Psychology,
University of Miami School of Medicine; CoDirector, E.M. Papper Laboratory of Clinical Immunology,
University Miami School of Medicine; Director of AIDS Research and CoDirector of AIDS Clinical
Research Unit, Miami VA Medical Center, Miami, FL, USA
A. Martin Lerner, MD, PC, MACP: Clinical Professor of Internal Medicine, Wayne State University School
of Medicine; William Beaumont Hospital, Royal Oak, MI, USA
Alison C. Bested, MD, FRCP(C): Haematological Pathologist; Environmental Health Clinic; Sunnybrook &
Women’s College Health Sciences Centre, Toronto, ON, Canada.
Pierre FlorHenry, MB, Ch B, MD, Acad DPM, FRC, CSPQ: Clinical Director, General Psychiatry;
Director, Clinical Diagnostics and Research Centre; Clinical Professor of Psychiatry, University of
Alberta, Edmonton, AB, Canada
Pradip Joshi, BM, MD, FRCP(C): Clinical Associate Professor, Memorial University of Newfoundland, St.
John’s, NF, Canada
A. C. Peter Powles, MRACP, FRACP, FRCP(C), ABSM: Professor Emeritus, Faculty of Health Sciences,
McMasters University, Hamilton, ON; Professor, Faculty of Medicine, University of Toronto; Chief of
Medicine and Sleep Disorder Consultant, St Joseph’s Health Centre, Toronto; Sleep Disorder Consultant
at the Sleep Disorder Clinic at St. Joseph’s Healthcare, Hamilton, and Central West Sleep Affiliation,
Paris, ON, Canada
Jeffrey A. Sherkey, MD, CCFP(C): Formerly in Family Medicine, University Health Network, Toronto, ON,
Canada. We sincerely regret that Dr. Sherkey has since passed away.
Marjorie I. van de Sande, B Ed, Grad Dip Ed: Consensus Coordinator; Advisor to the National ME/FM
Action Network, Canada
Acknowledgements for the Canadian Consensus Document
Lydia Neilson, MSM, President, and the National ME/FM Action Network for spearheading the drive for the
development of a clinical case definition, and diagnostic and treatment protocols for ME/CFS.
National ME/FM Action Network, Canada. www.mefmaction.net
Health Canada for establishing the “Terms of Reference” and selecting the Expert Consensus Panel
Crystaal, for sponsoring the Expert Consensus Panel Workshop without any direct involvement
James McSherry, MB, ChB, CCFP, FCFP, FABMP, FAAFP, who was a member of the Expert Consensus
Panel and contributed in the review process but was unable to attend the consensus meeting. We
sincerely regret that Dr. Mc Sherry has since passed away.
Kim D. Jones, RNC, Ph D, FNP, exercise physiologist, for her contribution to the exercise section.
Kerry Ellison, OT (nonpracticing), for her contribution to the patient management/treatment, and
assessing disability sections
Hugh Scher, LLP, for his contribution to the assessing disability section
Additional Acknowledgements for this Overview
Expert Consensus Panel for ME/CFS, for reviewing the overview
Robert J. van de Sande, B. Sc. E.E., for the cover design and formatting of the booklet
Pictures on Cover (Reprinted with permission): Dr. Floris de Lange sMRI voxelbased morphometry scan; Dr.
Pierre FlorHenry – qEEG topography; PET & Xenon SPECT scans: Goldstein JA. “Chronic Fatigue Syndromes:
The Limbic Hypothesis”. pp. vi, ix © 1993 Haworth Medical Press. Available from document delivery service:
Judith A. Brock, MA, for proofreading
A Clinical Case Definition and Guidelines for Medical Practitioners
An Overview of the Canadian Consensus Document iii
DEVELOPMENT OF THE CANADIAN CONSENSUS DOCUMENT
CLINICAL WORKING CASE DEFINTION OF ME/CFS
SYMPTOMS AND SIGNS
2. PostExertional Malaise and/or Fatigue
3. Sleep Dysfunction
5. Neurological/Cognitive Manifestations
6. Autonomic Manifestations
7. Neuroendocrine Manifestations
8. Immune Manifestations
Features of ME/CFS in Young People
CLINICAL EVALUATION OF ME/CFS
Differences Between ME/CFS and FMS
Differences Among ME/CFS and Psychiatric Disorders
SYMPTOM MANAGEMENT & TREATMENT
1. Sleep Disturbance
4. Cognitive Manifestations
5. Autonomic Manifestations
6. Neuroendocrine Manifestations
7. Immune Manifestations
Symptom Severity and Severity Hierarch Profile
Sleep and Pain Profile
Assessing Occupational Disability